Glucose Metabolic Flux Regulates NO and Pathologic Matrices in IPAH

关键词：肺动脉高压、一氧化氮、O-GlcNAc、葡萄糖、透明质酸、己糖胺特发性肺动脉高压（IPAH）是一种进展迅速、预后不良的心肺疾病。目前，IPAH被认为是一种由肺脉管系统形态学改变引起的血管病变。导致IPAH的分子基础尚未确定。此外，目前的治疗方法的有效性是有限的，因为它们不针对IPAH特征的特定进行性血管表型。代谢产物一氧化氮（NO）的生物利用度改变是该疾病的标志。随着NO缺乏，糖代谢失调在IPAH中得到了很好的描述。我们的长期目标是了解葡萄糖摄取/代谢失调和NO缺乏如何促进IPAH，并期望为该疾病设计治疗方法和预后指标。在IPAH中，多种过程由代谢功能失调控制，包括细胞增殖、炎症和血管重塑。有趣的是，IPAH患者的细胞外基质糖胺聚糖透明质酸（HA）也有所增加。然而，IPAH中(i)葡萄糖摄取/代谢失调，（ii） NO缺乏和（iii） HA产生之间的主要联系尚未阐明。更重要的是，IPAH中触发和延续这些不同表型的分子机制尚不清楚。该建议的中心假设是IPAH中HA生成增强和NO缺乏是由于葡萄糖摄取增加和己糖胺生物合成途径（HBP）的激活。这个假设是根据先前产生的初步数据制定的。我们提出这项研究的基本原理是旨在确定IPAH中葡萄糖代谢通量增加对NO缺乏和HA产生和功能的影响，以确定这些分子在IPAH中维持原代内皮和平滑肌细胞增殖、迁移和血管重塑中的调节作用。在强有力的初步数据的指导下，这一假设将通过两个具体目标进行验证：1)研究代谢通量调节IPAH中NO缺乏、血管增殖和重塑的机制；2)确定与己糖胺生物合成和HA产生异常相关的调控机制。这项研究具有重要意义，因为它将促进我们对HBP在IPAH中作为葡萄糖细胞传感器、NO产生调节剂和肺病理基质促进者的功能作用的理解。最终，这项工作将阐明HBP在IPAH病理生物学中对肺微环境的调节中的重要作用，并确定潜在的治疗靶点。

DESCRIPTION (provided by applicant): Glucose Metabolic Flux Regulates NO And Pathologic Matrices In IPAH Key Words: Pulmonary hypertension, Nitric oxide, O-GlcNAc, Glucose, Hyaluronan, hexosamine Idiopathic Pulmonary arterial Hypertension (IPAH) is a rapidly progressive cardiopulmonary disease with poor prognosis. Presently, IPAH is considered a vasculopathy resulting from morphological changes of the lung vasculature. The molecular underpinnings that cause IPAH have not been determined. In addition, the effectiveness of the present therapies is limited because they do not target specific progressive vascular phenotypes characterized in IPAH. The altered bioavailability of the metabolite nitric oxide (NO) is a hallmark of the disease. Along with NO deficiency, dysregulated glucose metabolism is well described in IPAH. Our long-term goal is to understand how dysregulated glucose uptake/metabolism and NO deficiency promote IPAH with the expectation to design therapeutic treatments and prognostic indicators for the disease. Multiple processes are governed by dysregulated metabolic function in IPAH including cellular proliferation, inflammation, and vascular remodeling. Interestingly, there is also an increase in the extracellular matrix glycosaminoglycan hyaluronan (HA) in IPAH. However, the primary link between (i) dysregulated glucose uptake/metabolism, (ii) NO deficiency and (iii) HA production in IPAH have not been elucidated. More importantly, the molecular mechanisms that trigger and perpetuate these different phenotypes in IPAH remains unclear. The central hypothesis of this proposal is that enhanced HA production and NO deficiency in IPAH result from increased glucose uptake and activation of the hexosamine biosynthetic pathway (HBP). The hypothesis has been formulated based on previously generated preliminary data. Our rationale for the proposed research is designed to establish the effects of increased glucose metabolic flux in IPAH on NO deficiency and HA production and function in order to determine the regulatory role(s) these molecules have in perpetuating primary endothelial and smooth muscle cell proliferation, migration, and vascular remodeling in IPAH. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Investigate the mechanisms whereby metabolic flux regulates NO deficiency, vascular proliferation and remodeling in IPAH; and 2) Determine the regulatory mechanisms associated with the abnormalities in hexosamine biosynthesis and HA production. The proposed research is significant, because it will advance our understanding of the functional role of the HBP as a glucose cellular sensor, regulator of NO production, and facilitator of lung pathological matrices in IPAH. Ultimately, the proposed work will shed light on the important role of the HBP in the regulation of the lung microenvironment in the pathobiology of IPAH and identify potential targets for therapy.